The synthesis of many useful compounds involves the coupling of two distinct chemical entities. Where those entities are an amine and an aldehyde, coupling is typically accomplished using reductive amination. For example, the preparation of arbutamine involves the reductive amination coupling of norepinephrine including free base and its salts, with 4-(4-benzyloxyphenyl)butanal to form benzyl arbutamine free base or its salt.
The use of reductive amination coupling to produce a desired product, free of contaminating byproducts, is compromised where the amine is a 1,2- or 1,3-aminoalcohol. The hydroxy group (OH) of the alcohol can react with the aldehyde to form an undesired cyclic amino acetal in addition to the desired hydroxyimine.
In the case of arbutamine preparation, formation of the oxazolidine leads to the synthesis of dialkylated byproducts through reaction of the oxazolidine with a second molecule of aldehyde present in the amination reaction. The presence of the dialkylated byproduct severely interferes with isolation of the desired monoalkylated product and decreases the yield of the desired product.
There continues to be a need for an improved process for the reductive amination of 1,2- or 1,3-aminoalcohols that prevents the formation of unwanted byproducts.